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Water → HCID 57978119, compound

HRID 2242320
Notes
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Reaction equation

HRID 2242320 reaction equation
C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[C:50]([NH:60][C@H:61]([C:66](O)=[O:67])[CH2:62][CH2:63][S:64][CH3:65])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>CCOC(C)=O.CC#N>[CH2:53]([O:52][C:50]([NH:60][C@@H:61]([CH2:62][CH2:63][S:64][CH3:65])[C:66]([NH:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:67])=[O:51])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 5

HCID 962WaterHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 1550857Benzyloxycarbonyl-L-methionineHCID 57454058HCID 57454058, compound

Product 1

HCID 57978119HCID 57978119, compound
Yield 98%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

Example 1, Alternative Step 9aii: Aminoester 1 (63 g, 0.16M, 1 eq.; the product of reductive deprotection of a known compound—(See e.g. R. J. Cherney, WO 2004/098516 and G. V. Delucca & S. S. Ko, WO 2004/110993) was placed in a round bottom flask and MeCN (500 mL) was added. EDAC (33.1 g, 0.17M, 1.1 eq), HOBt.H2O (21.2 g, 0.16M, 1.0 eq) and N-Cbz-L-methionine (46.7 g, 0.17M, 1.05 eq) were then added followed by TEA (48.0 mL, 0.35M, 2.2 eq). An exotherm to 38° C. was observed. The reaction mass was left to stir at RT. After 30 mins, HPLC indicated complete conversion. The reaction mass was diluted with EtOAc (2.5 L) and washed with KHCO3 (4×500 mL, 20 wt % aq. solution) and brine (500 mL). The organic phase was separated, dried over MgSO4 and concentrated. The residue was dissolved in TBME and reconcentrated to give ethyl (7R,8S)-8-{(2S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyr-yl-amino}-1,4-dioxa-spiro[4.5]decane-7-carboxylate 2 as a sticky semi-solid (76.2 g, 98% yield, 93 AP purity). 1H-NMR: (300 MHz, CDCl3) δ 7.36-7.30 (m, 5H), 7.03 (d, J 9.0 Hz, 1H), 5.66 (d, J 8.0 Hz, 1H), 5.10 (s, 2H), 4.35-4.25 (m, 2H), 4.19-4.04 (m, 2H,), 3.98-3.86 (m, 4H), 2.87-2.80 (m, 1H), 2.55-2.45 (m, 2H), 2.18 (dd, J 14.0 Hz, 7.0 Hz, 1H), 2.08 (s, 3H), 2.05-1.67 (m, 6H), 1.26 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 10.01 min (Compound 2, 93.1 AP). HRMS: m/z 495.2166 [Calc: C24H35N2O7S 495.2165].

Workup

  1. customKo, WO 2004/110993) was placed in a round bottom flask
  2. customto 38° C.
  3. waitThe reaction mass was left
  4. washwashed with KHCO3 (4×500 mL, 20 wt % aq. solution) and brine (500 mL)
  5. customThe organic phase was separated
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in TBME

Sources & evidence

ORD record
ord-b81909c8189b4e328a3e8af0ca204923
Source dataset
uspto-grants-2010_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07671062B2

Reaction notes

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